Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-07-02
2002-01-29
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S280000, C514S410000, C514S449000, C514S922000
Reexamination Certificate
active
06342487
ABSTRACT:
The present invention relates to compositions comprising at least one farnesyl transferase inhibitor compound and at least one topoisomerase inhibitor. The present invention also relates to compositions comprising at least one farnesyl transferase inhibitor together with at least one taxoid.
The protein farnesyl transferase is an enzyme which catalyses the transfer of the farnesyl group from farnesyl pyrophosphate (FPP) to the terminal cysteine residue of the CAAX tetrapeptide sequence of a certain number of proteins and, in particular, of the p2l Ras protein expressing the ras oncogene. The ras oncogene (H—, N— or K-ras) is known to play a key role in the routes of cell communication and the processes of cell division. The mutation of the ras oncogene or its overexpression is often associated with human cancer: the mutated p21Ras protein is found in numerous human cancers and especially in more than 50% of cancers of the colon and 90% of cancers of the pancreas (Kohl et al., Science, 260, 1834-1837, 1993). The inhibition of farnesyl transferase and consequently of farnesylation of the p21Ras protein blocks the capacity of the mutated p21Ras protein to induce cell proliferation and to transform normal cells into cancerous cells.
On the other hand, it has been demonstrated that the inhibitors of farnesyl transferase are likewise active on tumor cell lines not expressing mutated or overexpressed ras, but having the mutation of an oncogene or the overexpression of an oncoprotein whose route of communication uses the farnesylation of a protein, such as a normal ras (Nagasu et al., Cancer Research 55, 5310-5314, 1995; Sepp-Lorenzino et al., Cancer Research 55, 5302-5309, 1995).
The inhibitors of the farnesyl transferase protein are inhibitors of cell proliferation and consequently anti-tumor and anti-leukemic agents. In particular, the compounds described in U.S. application Ser. No. 08/999,408, filed on Dec. 29, 1997, now U.S. Pat. No. 6,013,662 the disclosure of which is specifically incorporated herein by reference, and the international application WO 98/29390, the disclosure of which is specifically incorporated herein by reference, are inhibitors of farnesyl transferase of very particular interest.
The topoisomerases are well-known enzymes which control the topology of the DNA in the course of replication, transcription and recombination. Two large classes of topoisomerases are known: the topoisomerases of type I, monomeric enzymes, catalyzing the opening/closing of a single strand of DNA; the topoisomerases of type II, multimeric enzymes, catalyzing these reactions on the two strands of DNA. Topoisomerases of type III are likewise known. See, e.g., Slichenmeyer et al. J Natl Cancer Inst 1993; 85: 271-291; Potmesil, Cancer Research 1994; 54: 1431-1439; Duguet et al., Medicine/Sciences 1994: 10: 962-972, Wall et al., J Am Chem Soc 1966; 88: 3888-3890, Gottlieb et al., Cancer Chemother Rep 1970; 54: 461-470, and Hsiang et al., Cancer Res 1988; 48: 1722-1726.
The topoisomerase inhibitors act by stabilization of the cleavage complex formed by the enzyme attached to the strand of DNA. This leads to the production of irreversible cleavages of the DNA, triggering a cell apoptosis program. Among the topoisomerase I inhibitors, it is especially possible to mention camptothecin and its derivatives; in particular topotecan and irinotecan (CPT-II). Among the topoisomerase II inhibitors, it is possible to mention epipodophyllotoxin derivatives such as etoposide and the anthracyclines.
Taxoids are anticancer agents suitable for administration to a patient in need thereof. Examples of taxoids include TAXOTERE® illustrated below:
TAXOTERE® is disclosed, for example, in U.S. Pat. Nos. 5,670,536 and 4,814,470, the disclosures of which are specifically incorporated by reference herein. Another taxoid example is:
i.e., 4&agr;-acetoxy-2&agr;-benzoyloxy-5&bgr;,20-epoxy-1&bgr;-hydroxy-7&bgr;,10&bgr;-dimethoxy-9-oxo-11-taxen-13&agr;-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate disclosed in U.S. Pat. No. 5,847,170, the disclosure of which is specifically incorporated by reference herein. Additional taxoids include TAXOL®, as disclosed in U.S. Pat. No. 5,254,580, at column 1, lines 21-33, which column 1 disclosure is specifically incorporated herein by reference, and 4&agr;-10&bgr;-diacetoxy-2&agr;-benzoyloxy-5&bgr;,20-epoxy-1&bgr;-hydroxy-7&bgr;,8&bgr;-methylene-9-oxo-19-nor-11-taxen-13&agr;-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate disclosed in U.S. Pat. No. 5,587,493, the disclosure of which is specifically incorporated herein by reference. Taxoids have been found to be therapeutically useful in anticancer treatments.
A subject of the present invention is improvement of the efficacy of farnesyl transferase inhibitor compounds when administered in combination with at least one topoisomerase inhibitor or when administered in combination with at least one taxoid. Within the meaning of the invention, “combination” is understood as including the association, including physical association, of, e.g., the at least one farnesyl transferase inhibitor compound and at least one topoisomerase inhibitor in which the compounds are present in separate form and can be administered separately, as well as situations where the molecules are not present in separate form in the combination.
Combination within the meaning of the invention is further defined as optionally including, in addition to:
(1) at least one farnesyl transferase inhibitor compound and at least one topoisomerase inhibitor and
(2) at least one taxoid with at least one farnesyl transferase inhibitor, at least one other substance therapeutically useful in the treatment of neoplastic diseases, chosen from:
the alkylating agents such as cyclophosphamide, ifosfamide, melphalan, hexamethylmelamine, thiotepa or dacarbazine,
antimetabolites such as pyridmine analogs such as 5-fluorouracil and cytarabine or its analogs such as 2-fluorodeoxycytidine or folic acid analogs such as methotrexate, idatrexate or trimetrexate,
spindle poisons including vinca alkaloids such as vinblastine or vincristine or their synthetic analogs such as navelbine, or estramustine or taxoids,
epipodophyllotoxins (a class of topoisomerase inhibitors), such as etoposide or teniposide,
antibiotics such as daunorubicin, doxorubicin, bleomycin or mitomycin,
enzymes such as L-asparaginase,
pyridobenzoindole derivatives and
various agents such as procarbazine, mitoxantrone, platinum coordination complexes such as cisplatin or carboplatin, biological response modifiers or growth factor inhibitors such as interferons or interleukins, or else growth factors of hematopoietic type such as G-CSF or GM-CSF, or radiotherapy.
A subject of the invention relates to the combinations comprising at least one farnesyl transferase inhibitor compound and at least one topoisomerase inhibitor; preferentially the combinations comprising a farnesyl transferase inhibitor with a topoisomerase inhibitor I inhibitor; the present invention also includes combinations comprising at least one farnesyl transferase inhibitor compound and at least one topoisomerase II inhibitor.
Another subject of the invention relates to the combinations comprising at least one taxoid and at least one farnesyl transferase inhibitor. In particular, the present invention relates to the combinations comprising at least one farnesyl transferase inhibitor and at least one taxoid, preferably chosen from TAXOL®, TAXOTERE®, and the other specific taxoids disclosed above.
A preferred aspect of the invention utilizes at least one farnesyl transferase inhibitor compound chosen from those described in U.S. application Ser. No. 08/999,408, filed on Dec. 29, 1997, now U.S. Pat. No. 6,013,662 the disclosure of which is specifically incorporated herein by reference, and the international application WO 98/29390, the disclosure of which is specifically incorporated herein by reference, of general formula (I):
in which:
Ar is
a phenyl radical substituted by one or more identical or different atoms or radica
Mailliet Patrick
Riou Jean-François
Vrignaud Patricia
Aventis Pharma Rorer S.A.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Krass Frederick
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